Catalyst-Free Visible-Light-Mediated Iodoamination of Olefins and Synthetic Applications

Article abstract of DOI:10.1021/acs.orglett.1c02035

Herein we report a catalyst- and metal-free visible-light-mediated protocol enabling the iodoamination of miscellaneous olefins. This protocol is characterized by high yields under environmentally benign reaction conditions utilizing commercially available substrates and a green and biodegradable solvent. Furthermore, the protocol allows for late-stage functionalization of bioactive molecules and can be scaled to gram quantities of product, which offers manifold possibilities for further transformations, including morpholine, piperidine, pyrrolidine, and aziridine synthesis.

Full text of DOI:10.1021/acs.orglett.1c02035

pubs.acs.org/OrgLett
Letter
Catalyst-Free Visible-Light-Mediated Iodoamination of Olefins and
Synthetic Applications
Sebastian Engl and Oliver Reiser*
Cite This: Org. Lett. 2021, 23, 5581−5586
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Herein we report a catalyst- and metal-free visible-
light-mediated protocol enabling the iodoamination of miscellaneous
olefins. This protocol is characterized by high yields under
environmentally benign reaction conditions utilizing commercially
available substrates and a green and biodegradable solvent.
Furthermore, the protocol allows for late-stage functionalization of
bioactive molecules and can be scaled to gram quantities of product,
which offers manifold possibilities for further transformations,
including morpholine, piperidine, pyrrolidine, and aziridine synthesis.
a
Table 1. Reaction Optimization
ioneered in the mid-1900s, aminohalogenation has
P
developed into a powerful tool in organic synthesis to
incorporate an amine as well as a halogen group into
unsaturated C−C bonds in a single step. The resulting vicinal
haloamine moiety represents a key motif in many bioactive
metabolites and can serve as a versatile intermediate in organic
synthesis.1 Consequently, a broad range of protocols for
chloroamination2,3 and bromoamination4 of unfunctionalized
double bonds have been disclosed. However, while impressive
work has been published on intramolecular iodoamination5
yielding various heterocyclic products, the analogous inter-
molecular ATRA-type iodoamination seems to be far less
explored. Recent seminal work describes this basic idea in only
limited examples6 and with difficulties in product isolation.7 It
is noteworthy that Li and co-workers8 described a thermal
iodoamination under mild conditions that gives the corre-
sponding products with different regioselectivity compared to
the present report via a closed-shell mechanism. Nonetheless,
especially when further synthetic transformations of the
corresponding halogen moieties are envisioned in order to
rapidly build up complex amine-containing molecules, the
highly reactive C−I bond might offer distinct advantages
against its lighter homologues. This fact is reflected by the lack
of further transformations for chloroamination of styrenes2 and
by the limited number of applications in bromoamination
studies.4e,g Motivated by this literature void, we aimed to
develop a broadly applicable protocol for the iodoamination of
various alkenes, which further can serve as versatile building
blocks for subsequent diversification and construction of
molecular complexity through simple operations.
b
entry
solvent 1:2:3 ratio
catalyst/condition
yield (%)
c
1
DCM
DCM
DCM
DCM
DCM
DMC
DMC
DMC
DMC
2:1:1
2:1:1
2:1:1
2:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
[Cu(dap)2]Cl (1 mol %)
[Ru(bpy)3]Cl2 (1 mol %)
fac-[Ir(ppy)3] (1 mol %)
−
−
−
dark reaction
dark reaction, T = 50 °C
under air
46
34
33
98
98
98
19
3
c d
,
2
3
4
5
6
7
8
9
c d
,
e
c
c
93
a
Reaction conditions: 0.5 mmol scale in the solvent (degassed, 0.25
M); irradiation at 530 nm under an atmosphere of N2 for 2 h at 25
b
c
d
°C. NMR yields. the reaction time was 24 h. Irradiation at 455 nm.
e
Isolated yield.
46% yield when [Cu(dap)2]Cl was used as the catalyst under
green LED irradiation (entry 1). Surprisingly, omitting the
photocatalyst in the reaction increased the yield of Ts-4a to
98%, providing a catalyst- and metal-free protocol (entry 4). In
accordance with our previous study,9 we assume that traces of
metal might inhibit free radical chain pathways of such
processes. Following the principles of green chemistry, it is
Received: June 18, 2021
Published: July 1, 2021
On the basis of our experience in the field of photocatalyzed
ATRA reactions,9 we started our investigations using styrene
(1a), N,4-dimethylbenzenesulfonamide (2a), NIS (3), and
various metal-based photocatalysts (Table 1, entries 1−3). The
desired iodoamination product Ts-4a was observed in up to
© 2021 The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.orglett.1c02035
Org. Lett. 2021, 23, 5581−5586
5581

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 1. Substrate Scope
a
Reaction conditions: 0.5 mmol scale in DMC (degassed); irradiation at 530 nm under an atmosphere of N2 for 2 h at 25 °C. Abbreviations: crm =
b
c
complex reaction mixture; nr = no reaction. The product could not be isolated. The NMR yield of the crude product is shown. 4.0 equiv of
alkene 1.
desirable to achieve high atom economy and replace
chlorinated solvents by more environmentally friendly and
preferable alternatives. Thus, we were pleased that also an
almost quantitative yield was also observed when the 1:2:3
molar ratio was changed to 1:1:1 and dimethyl carbonate
(DMC) was used as a green and biodegradable solvent (entries
5 and 6). Control experiments omitting light (entry 7) or
promoting the reaction under thermal activation (entry 8)
significantly decreased the yield of Ts-4a even after 24 h of
reaction time.
Next, we set out to explore the scope of the title reaction
(Scheme 1). Starting with activated alkenes (Scheme 1A),
electron-withdrawing halogen substitution was well-tolerated
at various positions, giving rise to the corresponding products
4b−f in high yields. Further increasing the electron-with-
drawing character of the styrene did not alter the reactivity and
the iodoamination products 4g−k were obtained in 77−96%
yield. Electron-donating alkyl substitution at the ortho, meta, or
para position still provided the desired products 4m−p in very
high yields. However, further increasing in the electron-
donating character by installing p-N(Me)2, p-SMe, or p-OMe
decreased the yield of the corresponding products 4r−t to 23−
36%. In line with this, when the OMe group was placed at the
meta position, thus acting as an acceptor, the desired
iodoamination product 4v was obtained in 93% yield. In the
same way, protection of the electron-donating alkoxy
substituent with an electron-withdrawing acetyl group at the
para position increased the yield of the corresponding product
4w to 95%. While α-substitution aiming at the synthesis of 4x
led to a complex reaction mixture, β-substitution proved to be
compatible, allowing the isolation of 4y in 90% yield.
Remarkably, a benzylic chloride-containing substrate, present-
ing a highly reactive benzylic C−H or C−Cl bond,
nevertheless showed no cross-reactivity and yielded 4z in
91% yield. We were pleased to see that vinylthiophene was also
an amenable substrate, thus giving access to 4aa in 62% yield.
Remarkably, the protocol was also capable of converting α,β-
unsaturated Michael systems to afford 4ae−ag in good yields
5582
https://doi.org/10.1021/acs.orglett.1c02035
Org. Lett. 2021, 23, 5581−5586

Organic Letters
pubs.acs.org/OrgLett
Letter
a
(Scheme 1B), even though the addition of electrophilic
radicals to such substrates is usually challenging. Besides
activated olefins, unactivated alkenes were also accessible in
this transformation by adjustment of the reaction stoichio-
metry (Scheme 1C). In this case, a large variety of different
functional groups were well-tolerated, giving rise to the desired
products 4ai−an in synthetically useful yields. Next, we
explored the scope of different amines in the iodoamination
of 1a (Scheme 1D). A broad range of functional groups were
tolerated, allowing rapid access to highly functionalized
molecules. The latter offer manifold possibilities to further
build up molecular complexity through simple operations,
which is demonstrated later on (see Scheme 3). Notably, a
primary tosylamide also leads to the desired ATRA product
4ap in excellent yield, enabling easy access to aziridines (see
Scheme 3E). Amino acid derivatives are suitable starting
materials in the same way, providing the desired products 4ay
and 4az in good yields. Sterically demanding adamantyl
substitution did not alter the reactivity, and iodoamination
product 4ba was obtained in 56% yield. A limitation was found
when the tosyl group was replaced by a Boc group, leading to
no conversion of the starting materials to 4bb. However,
considering that the nosyl group is a much milder removable
sulfonyl protecting group compared with the tosyl group,10 we
were very pleased to observe that the nosyl group was tolerated
in the same way, as demonstrated by selected representative
examples (Ns-4a, Ns-4e, Ns-4i, Ns-4o, Ns-4w, Ns-4ae, Ns-
4ah) in comparable yields.
Scheme 3. Synthetic Utility
We next investigated the late-stage functionalization of more
complex, biologically active molecules (Scheme 2). Estrone-,
a
Scheme 2. Late-Stage Functionalizations
a
Reaction conditions: reactions were conducted on a 0.3 mmol scale.
(a) 4a in acetone/water (1:1) for 12 h at 100 °C. (b) 4a and FeCl3·
6H2O (4.0 equiv) in MeCN for 2 h at 80 °C. (c) 4a and NaN3 (5.0
equiv) in DMF for 5 h at 25 °C. (d) 4a and NaOAc (10.0 equiv) in
DMF for 5 h at 25 °C. (e) 4a, Bu3SnH (3.0 equiv), and AIBN (10
mol %) in benzene for 12 h at 80 °C. (f) 4a, thiophenol (2.5 equiv),
and Na2CO3 (2.5 equiv) in MeCN for 24 h at 25 °C. (g) 4a and
NaSCN (5.0 equiv) in DMF for 24 h at 70 °C. (h) 4a in MeOH for
12 h at 65 °C. (i) See Scheme 1. (j) 4ax and TBAF (1.2 equiv) in
THF for 1 h at 25 °C. (k) 4as, NiI2 (10 mol %), 2,2′-bipyridine (10
mol %), and Zn (3.0 equiv) in DMA for 16 h at 25 °C. (l) 1a (0.5
mmol, 1.0 equiv), 2bf (1.0 equiv), and 3 (1.0 equiv) in DMC
(degassed); irradiation at 530 nm under N2 for 2 h at 25 °C. (m) 4ap
and NEt3 (3.0 equiv) in DCM for 3 h at 25 °C. (n) Ns-5 (0.2 mmol),
2-mercaptoacetic acid (6.0 equiv), and DBU (6.0 equiv) in DMF for
12 h at 25 °C. (o) 21 and Mg (10 equiv) in MeOH for 3 h at 25 °C.
Ref [a].12 Ref [b].13 Ref [c].14
a
Reaction conditions: 0.5 mmol scale in DMC (degassed); irradiation
at 530 nm under an atmosphere of N2 for 2 h at 25 °C.
fenofibrate-, and vitamin E-derived substrates were successfully
transformed to the desired iodoamination products 4bc−be in
good to excellent yields, showcasing the capacity of the
protocol in multistep synthesis of complex molecules. Next, we
established the viability of the protocol for preparative
purposes. When the scale was increased by a factor of 10,
the iodoamination product Ts-4a was obtained in multigram
amounts in an almost quantitative yield of 97% in a simple
batch setup without the necessity to prolong the reaction time
(Scheme 3). Given the scarcity of synthetic utility of the
corresponding benzylic 1,2-chloro-2 and 1,2-bromoamination
compounds,4e,g we were pleased to find that the benzylic
iodides offer manifold possibilities for further transformations.
Various nucleophiles can smoothly be introduced, leading to a
whole family of 1,2-functionalized amines. For example,
substitution with oxygen nucleophiles delivers not only methyl
ether 7 from Ts-4a but also 1,2-amino alcohols Ts-5 and Ns-5
from the tosyl- and nosyl-protected amines, respectively,
representing a key structural motif in biologically active
compounds as well as being important in coordination
chemistry.11 In the same way, sulfur nucleophiles can be
applied to access 1,2-amino thiols 12 and 13, while nitrogen
nucleophiles give rise to 1,2-diamines 8 and 9. Elimination of
5583
https://doi.org/10.1021/acs.orglett.1c02035
Org. Lett. 2021, 23, 5581−5586

Organic Letters
pubs.acs.org/OrgLett
Letter
Ts-4a smoothly provides access to the corresponding enamine
10 in high yields, whereas dehalogenation provides the
analogous amine 11.
(Scheme 4B). The reaction of diene 1bi and amine 2a together
with NIS gave rise to product 4bi with exclusive 1,4-selectivity
(Scheme 4C). The quantum yield of the reaction was
determined to be 125%, clearly pointing toward a radical
chain mechanism (Scheme 4D). Hence, in agreement with a
very recent study on the halogen-bond-induced C−H
amination initiated by 4-methylbenzenesulfonamide and
NIS,7 we propose the following mechanism (Scheme 5).
Simple deprotection of substrate 4ax bearing a protected
alcohol moiety gives rise to the substrate class of morpholines
14, which possess great importance in bioorganic chemistry.15
Transition metal catalysis offers the opportunity to insert Ni
into the C−I bond, thus triggering intramolecular cyclization
in compound 4as to rapidly form 3-aryl-substituted piper-
idines, which have been investigated since the early 1980s in
view of their dopaminergic activities and usually require harsh
reaction conditions for their synthesis.16 Subjecting allylamine
2bf to the reaction conditions provided the opportunity for in
situ radical 5-exo-trig cyclization to access pyrrolidine
derivative 17 in a single step from commercially available
bulk chemicals. Notably, analogous chloroamination protocols
require either harsh radical conditions17 or expensive Ir-based
photocatalysis.18 Treatment of photoproduct 4ap with base
smoothly leads to the substrate class of aziridines 18,
representing privileged structural motifs in organic chemistry.19
We next investigated the tosyl and nosyl deprotection for
representative examples (Scheme 3F). While morpholine
derivative 14 and piperidine 15 can smoothly be tosyl-
deprotected under mild reductive conditions, the introduced
nosyl goup offers the possibility to deprotect more function-
alized molecules like Ns-5 under much milder redox-neutral
conditions, giving halostachine (20) in good yields.
Scheme 5. Proposed Reaction Mechanism
First, the halogen bond complex I absorbs visible light, leading
to visible-light-induced homolysis and generation of complex
II. Extensive mechanistic investigations of the aforementioned
study revealed this activation mode of such substrates.7 After
charge- and proton transfer, the iodine radical IV and the
nitrogen-centered radical VI get extruded. The latter adds to
the alkene 1, forming radical intermediate VII, which now can
abstract iodide from the starting complex I to deliver the final
product 4 with concurrent regeneration of nitrogen-centered
radical VI. Notably, this principle of photochemical iodide
activation can be also found with phosphines.20
In conclusion, we have developed a highly efficient protocol
to directly furnish a broad scope of iodoamination of
commercially available alkenes utilizing simple and abundant
sulfonamides and NIS under visible-light irradiation. The
protocol excels through high yields and environmentally
benign reaction conditions, omitting any metal or catalyst
species and being driven in a green and biodegradable solvent.
The protocol is robust and insensitive to air and allows for late-
stage functionalization of biologically active molecules. For
preparative purposes it can be smoothly scaled to gram
quantities of the products, which offer a plethora of further
synthetic transformations. Nucleophilic substitution with
manifold nucleophiles provides a library of 1,2-functionalized
amines, including amino alcohols, amino thiols, and diamines.
Furthermore, several classes of biologically important hetero-
cycles can be rapidly accessed using the iodoamination
products as starting points, including morpholines, piperidines,
pyrrolidines, and aziridines.
In line with a mechanistic pathway calling for radical
intermediates, the addition of TEMPO to the standard
reaction conditions resulted in complete shutdown of the
reaction, while the TEMPO trapping adduct 4bg was detected
by HRMS (Scheme 4A). A radical clock experiment subjecting
1bh to the reaction conditions exclusively led to the formation
of product 4bh, in agreement with radical intermediate 23,
which undergoes radical-initiated ring opening to give 24
a
Scheme 4. Mechanistic Investigations
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02035.
(Experimental details, further optimization, full charac-
terization data, detailed calculation of the quantum yield,
and copies of NMR spectra PDF)
a
Reaction conditions: 0.5 mmol scale in DMC (degassed, 2.0 mL,
0.25 M); irradiation at 530 nm under an atmosphere of N2 for 2 h at
25 °C.
5584
https://doi.org/10.1021/acs.orglett.1c02035
Org. Lett. 2021, 23, 5581−5586

Organic Letters
pubs.acs.org/OrgLett
Letter
TsNH2 and NBS as nitrogen and bromine sources. Org. Lett. 2003, 5,
861−864. (c) Yeung, Y.-Y.; Gao, X.; Corey, E. J. A general process for
the haloamidation of olefins. Scope and mechanism. J. Am. Chem. Soc.
2006, 128, 9644−9645. (d) Shaikh, T. M.; Karabal, P. U.;
Suryavanshi, G.; Sudalai, A. Titanium superoxide: a heterogeneous
catalyst for anti-Markovnikov aminobromination of olefins. Tetrahe-
dron Lett. 2009, 50, 2815−2817. (e) Zhang, G.; An, G.; Zheng, J.;
Pan, Y.; Li, G. Catalyst-free aminobromination of alkenes with N-
methyl-p-toluenesulfonamide as nitrogen resource. Tetrahedron Lett.
2010, 51, 987−989. (f) Song, L.; Luo, S.; Cheng, J.-P. Visible-light
promoted intermolecular halofunctionalization of alkenes with N-
halogen saccharins. Org. Chem. Front. 2016, 3, 447−452. (g) Yu, W.
Z.; Cheng, Y. an; Wong, M. W.; Yeung, Y.-Y. Atmosphere- and
Temperature-Controlled Regioselective Aminobromination of Ole-
fins. Adv. Synth. Catal. 2017, 359, 234−239.
AUTHOR INFORMATION
Corresponding Author
■
Oliver Reiser − Institute of Organic Chemistry, University of
Regensburg, 93053 Regensburg, Germany; orcid.org/
0000-0003-1430-573X; Email: oliver.reiser@
chemie.uniregensburg.de
Author
Sebastian Engl − Institute of Organic Chemistry, University of
Regensburg, 93053 Regensburg, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02035
Notes
(5) For selected examples of intramolecular iodoamination, see:
(a) Mizar, P.; Burrelli, A.; Gunther, E.; Söftje, M.; Farooq, U.; Wirth,
̈
The authors declare no competing financial interest.
T. Organocatalytic stereoselective iodoamination of alkenes. Chem. -
Eur. J. 2014, 20, 13113−13116. (b) Sun, H.; Cui, B.; Liu, G.-Q.; Li,
Y.-M. MnI2-catalyzed regioselective intramolecular iodoamination of
unfunctionalized olefins. Tetrahedron 2016, 72, 7170−7178.
(c) Chen, L.; Luo, X.; Li, Y. Palladium-catalyzed intramolecular
aminoiodination of alkenes using molecular oxygen as oxidant.
Monatsh. Chem. 2017, 148, 957−961. (d) Struble, T. J.; Lankswert, H.
M.; Pink, M.; Johnston, J. N. Enantioselective Organocatalytic Amine-
Isocyanate Capture-Cyclization: Regioselective Alkene Iodoamination
for the Synthesis of Chiral Cyclic Ureas. ACS Catal. 2018, 8, 11926−
ACKNOWLEDGMENTS
This work was supported by the Studienstiftung des Deutschen
Volkes and the Elite Network of Bavaria.
■
REFERENCES
■
(1) For recent reviews of haloamination, see: (a) Li, G.; Kotti, S. R.
S. S.; Timmons, C. Recent Development of Regio- and Stereoselective
Aminohalogenation Reaction of Alkenes. Eur. J. Org. Chem. 2007,
2007, 2745−2758. (b) Chemler, S. R.; Bovino, M. T. Catalytic
Aminohalogenation of Alkenes and Alkynes. ACS Catal. 2013, 3,
1076−1091. (c) Wu, Z.; Hu, M.; Li, J.; Wu, W.; Jiang, H. Recent
advances in aminative difunctionalization of alkenes. Org. Biomol.
Chem. 2021, 19, 3036−3054.
̀
11931. (e) Giofre, S.; Sala, R.; Beccalli, E. M.; Lo Presti, L.; Broggini,
G. Iodoamination of Alkenyl Sulfonamides by Potassium Iodide and
Hydrogen Peroxide in Aqueous Medium. Helv. Chim. Acta 2019, 102,
e1900088.
(6) (a) Yang, X.; Yudin, A. Facile Generation and Synthetic Utility
of Nitrogen-Centered Aziridinyl Radicals. Synlett 2007, 2007, 2912−
2918. (b) Liu, G.-Q.; Li, Y.-M. Regioselective (diacetoxyiodo)-
benzene-promoted halocyclization of unfunctionalized olefins. J. Org.
Chem. 2014, 79, 10094−10109.
(7) Wu, F.; Ariyarathna, J. P.; Kaur, N.; Alom, N.-E.; Kennell, M. L.;
Bassiouni, O. H.; Li, W. Halogen-Bond-Induced Consecutive Csp3-H
Aminations via Hydrogen Atom Transfer Relay Strategy. Org. Lett.
2020, 22, 2135−2140.
(8) Lei, B.; Miao, Q.; Ma, L.; Fu, R.; Hu, F.; Ni, N.; Li, Z. Efficient
metal-free aminoiodination of alkenes with N-fluorobenzenesulfoni-
mide under mild conditions. Org. Biomol. Chem. 2019, 17, 2126−
2133.
(9) Engl, S.; Reiser, O. Copper Makes the Difference: Visible Light-
Mediated Atom Transfer Radical Addition Reactions of Iodoform
with Olefins. ACS Catal. 2020, 10, 9899−9906.
(10) Fukuyama, T.; Jow, C.-K.; Cheung, M. 2- and 4-Nitro-
benzenesulfonamides: Exceptionally versatile means for preparation of
secondary amines and protection of amines. Tetrahedron Lett. 1995,
36, 6373−6374.
(11) Ager, D. J.; Prakash, I.; Schaad, D. R. 1,2-Amino Alcohols and
Their Heterocyclic Derivatives as Chiral Auxiliaries in Asymmetric
Synthesis. Chem. Rev. 1996, 96, 835−876.
(12) Galstyan, T. M.; Galstyan, G. A.; Yakobi, V. A. Oxidation of 1-
phenyl-2-(N-methyl-p-toluenesulfonamido) ethanol by an ozone-air
mixture. Zh. Prikl. Khim. 1985, 2681−2685.
(13) Hamada, T.; Nishida, A.; Yonemitsu, O. Selective removal of
electron-accepting p-toluene- and naphthalenesulfonyl protecting
groups for amino function via photoinduced donor acceptor ion
pairs with electron-donating aromatics. J. Am. Chem. Soc. 1986, 108,
140−145.
(2) For selected examples of chloroamination of activated alkenes,
see: (a) Li, G.; Wei, H.-X.; Kim, S. H. Unexpected copper-catalyzed
aminohalogenation reaction of olefins using N-halo-N-metallo-
sulfonamide as the nitrogen and halogen sources. Tetrahedron 2001,
57, 8407−8411. (b) Minakata, S.; Yoneda, Y.; Oderaotoshi, Y.;
Komatsu, M. Unprecedented CO2-promoted aminochlorination of
olefins with Chloramine-T. Org. Lett. 2006, 8, 967−969. (c) Martínez,
C.; Muniz, K. A versatile metal-free Intermolecular Aminochlorination
̃
of Alkenes. Adv. Synth. Catal. 2014, 356, 205−211. (d) Qin, Q.; Ren,
D.; Yu, S. Visible-light-promoted chloramination of olefins with N-
chlorosulfonamide as both nitrogen and chlorine sources. Org. Biomol.
Chem. 2015, 13, 10295−10298. (e) Heuger, G.; Göttlich, R.
Intermolecular addition reactions of N-alkyl-N-chlorosulfonamides
to unsaturated compounds. Beilstein J. Org. Chem. 2015, 11, 1226−
1234. (f) Jolley, K. E.; Chapman, M. R.; Blacker, A. J. A general and
atom-efficient continuous-flow approach to prepare amines, amides
and imines via reactive N-chloramines. Beilstein J. Org. Chem. 2018,
14, 2220−2228.
(3) For selected examples of chloroamination of unactivated alkenes,
see: (a) Legnani, L.; Prina-Cerai, G.; Delcaillau, T.; Willems, S.;
Morandi, B. Efficient access to unprotected primary amines by iron-
catalyzed aminochlorination of alkenes. Science 2018, 362, 434−439.
(b) Li, Y.; Liang, Y.; Dong, J.; Deng, Y.; Zhao, C.; Su, Z.; Guan, W.;
Bi, X.; Liu, Q.; Fu, J. Directed Copper-Catalyzed Intermolecular
Aminative Difunctionalization of Unactivated Alkenes. J. Am. Chem.
Soc. 2019, 141, 18475−18485. (c) Falk, E.; Makai, S.; Delcaillau, T.;
Gurtler, L.; Morandi, B. Design and Scalable Synthesis of N-
̈
Alkylhydroxylamine Reagents for the Direct Iron-Catalyzed Installa-
tion of Medicinally Relevant Amines. Angew. Chem., Int. Ed. 2020, 59,
21064−21071. (d) Govaerts, S.; Angelini, L.; Hampton, C.; Malet-
Sanz, L.; Ruffoni, A.; Leonori, D. Photoinduced Olefin Diamination
(14) Ritzen, B.; Hoekman, S.; Verdasco, E. D.; van Delft, F. L.;
Rutjes, F. P. J. T. Enantioselective chemoenzymatic synthesis of cis-
and trans-2,5-disubstituted morpholines. J. Org. Chem. 2010, 75,
3461−3464.
(15) Kourounakis, A. P.; Xanthopoulos, D.; Tzara, A. Morpholine as
a privileged structure: A review on the medicinal chemistry and
with Alkylamines. Angew. Chem., Int. Ed. 2020, 59, 15021−15028.
́
́
(4) For selected examples of bromoamination, see: (a) Sliwinska, A.;
Zwierzak, A. Ionic addition of t-butyl N,N-dibromocarbamate (BBC)
to alkenes and cycloalkenes. Tetrahedron Lett. 2003, 44, 9323−9325.
(b) Thakur, V. V.; Talluri, S. K.; Sudalai, A. Transition metal-
catalyzed regio- and stereoselective aminobromination of olefins with
5585
https://doi.org/10.1021/acs.orglett.1c02035
Org. Lett. 2021, 23, 5581−5586

Organic Letters
pubs.acs.org/OrgLett
Letter
pharmacological activity of morpholine containing bioactive mole-
cules. Med. Res. Rev. 2020, 40, 709−752.
(16) Chang, M.-Y.; Hsu, R.-T.; Chen, H.-P.; Lin, P.-J. Concise
Synthesis of 3-Arylpiperidines. Heterocycles 2006, 68, 1173.
(17) Tsuritani, T.; Shinokubo, H.; Oshima, K. Radical [3 + 2]
annulation of N-allyl-N-chlorotosylamide with alkenes via atom-
transfer process. Org. Lett. 2001, 3, 2709−2711.
(18) Crespin, L. N. S.; Greb, A.; Blakemore, D. C.; Ley, S. V. Visible-
Light-Mediated Annulation of Electron-Rich Alkenes and Nitrogen-
Centered Radicals from N-Sulfonylallylamines: Construction of
Chloromethylated Pyrrolidine Derivatives. J. Org. Chem. 2017, 82,
13093−13108.
(19) Ghorai, M. K.; Bhattacharyya, A.; Das, S.; Chauhan, N. Ring
expansions of activated aziridines and azetidines. Top. Heterocycl.
Chem. 2015, 41, 49−142.
(20) For recent examples of iodine activation with phosphines, see:
(a) Wulkesch, C.; Czekelius, C. Straightforward Synthesis of
Fluorinated Enals via Photocatalytic α-Perfluoroalkenylation of
Aldehydes. J. Org. Chem. 2021, 86, 7425−7438. (b) Helmecke, L.;
Spittler, M.; Schmidt, B. M.; Czekelius, C. Metal-Free Iodoper-
fluoroalkylation: Photocatalysis versus Frustrated Lewis Pair Catalysis.
Synthesis 2021, 53, 123−134.
5586
https://doi.org/10.1021/acs.orglett.1c02035
Org. Lett. 2021, 23, 5581−5586